DOCSLIB.ORG

Orexin a Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope Att20 Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Orexin a Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope Att20 Cells International Journal of Molecular Sciences Article Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells Satoshi Fujisawa 1, Motoshi Komatsubara 1, Naoko Tsukamoto-Yamauchi 1, Nahoko Iwata 2, Takahiro Nada 2, Jun Wada 1 and Fumio Otsuka 2,* 1 Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan; [email protected] (S.F.); swe_etfi[email protected] (M.K.); [email protected] (N.T.-Y.); [email protected] (J.W.) 2 Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan; nao53mayfl[email protected] (N.I.); [email protected] (T.N.) * Correspondence: [email protected]; Tel.: +81-86-235-7342; Fax: +81-86-222-7345 Abstract: Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic– pituitary–adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed Citation: Fujisawa, S.; Komatsubara, in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor M.; Tsukamoto-Yamauchi, N.; Iwata, mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced N.; Nada, T.; Wada, J.; Otsuka, F. POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregu- Orexin A Enhances lation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription Pro-Opiomelanocortin Transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA Regulated by BMP-4 in Mouse expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the Corticotrope AtT20 Cells. Int. J. Mol. expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and Sci. 2021, 22, 4553. https://doi.org/ 10.3390/ijms22094553 protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by Academic Editors: corticotrope cells. Kazunori Kageyama and Takahiro Nemoto Keywords: anterior pituitary; bone morphogenetic protein (BMP); corticotrope; orexin; pro-opiomelanocortin (POMC) Received: 15 March 2021 Accepted: 25 April 2021 Published: 27 April 2021 1. Introduction Publisher’s Note: MDPI stays neutral Orexins are neuropeptides that are expressed primarily in the hypothalamus and with regard to jurisdictional claims in are produced in two isoforms, orexin A (ORX) and orexin B, from a common precursor published maps and institutional affil- protein, prepro-orexin [1]. There are two types of G protein-coupled receptors, named iations. orexin type 1 (OX1R) and type 2 (OX2R) receptors. Orexin B binds only to OX2R, while orexin A binds to both OX1R and OX2R [2]. Since its discovery in 1998, orexin has been reported to have various effects on sleep–wake regulation, feeding behavior, emotions, and the autonomic nervous system involved in stress control [1,3,4]. Orexin is also known to Copyright: © 2021 by the authors. have physiological effects in peripheral tissues, including the endocrine system [5]. Licensee MDPI, Basel, Switzerland. An interaction between the hypothalamic–pituitary–adrenal (HPA) system in response This article is an open access article to stressful stimuli and orexin neurons has been recognized. Orexin has been reported distributed under the terms and to enhance adrenocortical hormone secretion [6,7] in the HPA axis, and orexin neurons conditions of the Creative Commons are further activated by corticotropin-releasing hormone (CRH) [8]. Previous studies Attribution (CC BY) license (https:// showed that an intracerebroventricular injection of orexin increased adrenocorticotropin creativecommons.org/licenses/by/ 4.0/). (ACTH) and corticosterone levels in the blood, which were reversed by CRH receptor Int. J. Mol. Sci. 2021, 22, 4553. https://doi.org/10.3390/ijms22094553 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4553 2 of 10 inhibitors [9–11]. Moreover, that orexin increases CRH and arginine vasopressin (AVP) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus [12]. These results suggested that orexin plays an important role in regulating the HPA axis, which is involved in stress responses, mainly in the hypothalamus. Moreover, in the adrenal cortex, it was shown that orexin A rather than orexin B directly stimulates corticosterone secretion in adrenal cortical cells and that this effect is not blunted by ACTH receptor antagonists [13,14]. Those studies showed that orexin has a functional role in the adrenal cortex, independent of ACTH-stimulated control. ACTH is produced from the precursor protein pro-opiomelanocortin (POMC), which is synthesized in corticotrope cells. POMC is also cleaved into multiple peptide hormones in the pituitary and hypothalamus. POMC neurons are located in the arcuate nucleus of the hypothalamus; they suppress appetite, regulate energy balances, and are thought to be involved in the mechanism of orexin-mediated feeding behavior [15]. Increasing evidence has shown a mutual relationship between orexin, the HPA axis, and POMC in the hypothalamus. Given the finding that OX2R was expressed in human corticotrope cells, orexin might be directly involved in the mechanism of hormone production by the anterior pituitary [16]. There has been growing evidence that BMPs, members of the transforming growth factor (TGF)β superfamily of proteins, play functional roles in various endocrine organs in an autocrine or paracrine manner [17]. In pituitary corticotrope AtT20 cells, BMP-4 is known to inhibit the tumorigenesis of corticotrope tumor cells [18,19]. We previously reported that BMP-4 was involved in the suppression of ACTH secretion by somatostatin receptor stimulation and also suppressed GHRP-2-induced ACTH secretion in AtT20 cells [20,21]. Interestingly, we recently revealed that orexin inhibits prolactin secretion by suppressing BMP signaling in rat somatolactotrope GH3 cells [22]. In the present study, we investigated the role of orexin in endocrine regulation in the pituitary gland, focusing on the relationship of orexin with BMP signaling by using the mouse pituitary corticotrope tumor cell line AtT20. 2. Results First, we evaluated the expression of orexin receptors in AtT20 cells. Although the expression of both OX1R and OX2R was detected in mouse pituitary gonadotrope LβT2 cells by RT-PCR, AtT20 cells mainly expressed OX2R, as shown in Figure1A. AtT20 cells express CRHR1 as a receptor for CRH, and orexin A (100 nM) treatment enhanced the mRNA expression of CRHR1. To determine whether this orexin-induced change in the CRH receptor was also detectable at protein levels, Western blotting was performed. As shown in Figure1B, orexin A (100 nM) treatment for 48 h increased the protein expression level of CRHR1 in a time-dependent manner. Therefore, we examined the function of orexin in CRH signaling in AtT-20 cells. Treatment with orexin A (10–300 nM) did not change basal mRNA levels of POMC for 24 h. However, in the presence of CRH (100 nM), co-treatment with orexin (10–300 nM) for 24 h enhanced CRH-induced mRNA expression of POMC (Figure1C). Next, we examined the effect of orexin on the action of BMP-4 in AtT-20 cells. We previously reported that BMP-4 suppressed POMC mRNA expression in AtT20 cells [20]. As shown in Figure2A, BMP-4 (10 ng/mL) treatment for 24 h decreased POMC mRNA, consistent with the results of our previous study. Co-treatment with orexin (10–100 nM) did not change the POMC mRNA expression induced by BMP-4 treatment from 1 h to 24 h (Figure2A). On the other hand, focusing on the effect of orexin on BMP-Smad signaling, stimulation with BMP-4 (10 ng/mL) for 1 h activated Smad1/5/9 phosphorylation in AtT20 cells (Figure2B). Importantly, orexin A (100 nM) pretreatment for 24 h inhibited the phosphorylation of Smad1/5/9 by BMP-4 (Figure2B). We next examined the effect of orexin A on the transcription of Id-1, a target gene for BMP-receptor signaling. As shown in Figure2C, BMP-4 (10 ng/mL) treatment for 1 h significantly upregulated Id-1 mRNA, Int. J. Mol. Sci. 2021, 22, 4553 3 of 10 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 10 and co-treatment with orexin A (100 nM) suppressed the expression of Id-1 mRNA induced by BMP-4. Figure 1. Expression of orexin receptors and the effect of orexin A on CRH CRH receptor receptor and and POMC POMC expression expression in in AtT20 AtT20 cells. cells. (A) The expression expression of of mRNAs mRNAs encoding encoding OX1R, OX1R, OX2R OX2R,, and and RPL19 RPL19 was was examined examined by RT by− RTPCR−PCR in AtT20 in AtT20 cells cellscompared compared with withthat in that mouse in mouse gonadotrope gonadotrope LβT2 Lcells.βT2 MM: cells. molecular MM: molecular weight weight marker. marker. (B) After (B) preculture, After preculture, cells were cells treated were treated with orexin with (ORX)orexin in (ORX) serum in-free serum-free media. After media. 24− Afterh culture, 24-h total culture, cellular total RNA cellular was RNAextracted, was and extracted, after 24 and−h or after 48−h 24-h culture, or 48-h cellculture, lysates werecell lysates extracted. were The extracted. mRNA Theexpression mRNA levels expression of Crhr1 levels were of quantified Crhr1 were by quantified qPCR, and by the qPCR, expression and the levels expression of target levels genes of weretarget standardized genes were standardized by the RPL19 by thelevel RPL19 in each level sample.
Load more

Recommended publications
  • The Hypothalamus and the Regulation of Energy Homeostasis: Lifting the Lid on a Black Box
    Proceedings of the Nutrition Society (2000), 59, 385–396 385 CAB59385Signalling39612© NutritionInternationalPNSProceedings Society in body-weight 2000 homeostasisG. of the Nutrition Williams Society et (2000)0029-6651©al.385 Nutrition Society 2000 593 The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box Gareth Williams*, Joanne A. Harrold and David J. Cutler Diabetes and Endocrinology Research Group, Department of Medicine, The University of Liverpool, Liverpool L69 3GA, UK Professor Gareth Williams, fax +44 (0)151 706 5797, email [email protected] The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of ‘feeding’ and ‘satiety’ centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor.
    [Show full text]
  • Activation of Orexin System Facilitates Anesthesia Emergence and Pain Control
    Activation of orexin system facilitates anesthesia emergence and pain control Wei Zhoua,1, Kevin Cheunga, Steven Kyua, Lynn Wangb, Zhonghui Guana, Philip A. Kuriena, Philip E. Bicklera, and Lily Y. Janb,c,1 aDepartment of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143; bDepartment of Physiology, University of California, San Francisco, CA 94158; and cHoward Hughes Medical Institute, University of California, San Francisco, CA 94158 Contributed by Lily Y. Jan, September 10, 2018 (sent for review May 22, 2018; reviewed by Joseph F. Cotten, Beverley A. Orser, Ken Solt, and Jun-Ming Zhang) Orexin (also known as hypocretin) neurons in the hypothalamus Orexin neurons may play a role in the process of general an- play an essential role in sleep–wake control, feeding, reward, and esthesia, especially during the recovery phase and the transition energy homeostasis. The likelihood of anesthesia and sleep shar- to wakefulness. With intracerebroventricular (ICV) injection or ing common pathways notwithstanding, it is important to under- direct microinjection of orexin into certain brain regions, pre- stand the processes underlying emergence from anesthesia. In this vious studies have shown that local infusion of orexin can shorten study, we investigated the role of the orexin system in anesthe- the emergence time from i.v. or inhalational anesthesia (19–23). sia emergence, by specifically activating orexin neurons utilizing In addition, the orexin system is involved in regulating upper the designer receptors exclusively activated by designer drugs airway patency, autonomic tone, and gastroenteric motility (24). (DREADD) chemogenetic approach. With injection of adeno- Orexin-deficient animals show attenuated hypercapnia-induced associated virus into the orexin-Cre transgenic mouse brain, we ventilator response and frequent sleep apnea (25).
    [Show full text]
  • OREXIN ANTAGONISTS BELSOMRA (Suvorexant), DAYVIGO (Lemborexant)
    OREXIN ANTAGONISTS BELSOMRA (suvorexant), DAYVIGO (lemborexant) RATIONALE FOR INCLUSION IN PA PROGRAM Background Belsomra (suvorexant) and Dayvigo (lemborexant) are orexin receptor antagonists used to treat difficulty in falling and staying asleep (insomnia). Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake (1-2). Regulatory Status FDA-approved indication: Orexin receptor antagonists are indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance (1-2). Orexin Antagonists are contraindicated in patients with narcolepsy (1-2). Orexin Antagonists are central nervous system (CNS) depressants that can impair daytime wakefulness even when used as prescribed. Medications that treat insomnia can cause next-day drowsiness and impair driving and other activities that require alertness. Orexin Antagonists can impair driving skills and may increase the risk of falling asleep while driving. People can be impaired even when they feel fully awake. Patients should also be made aware of the potential for next-day driving impairment, because there is individual variation in sensitivity to the drug (1-2). The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or mental illness that should be evaluated (1-2). Warnings and precautions that should be discussed with the patient on Orexin Antagonist therapy include adverse reactions on abnormal thinking and behavioral changes (such as amnesia, anxiety, hallucinations and other neuropsychiatric symptoms), complex behaviors (such as sleep- driving, preparing and eating food, or making phone calls), dose-dependent increase in suicidal ideation, and sleep paralysis which is the inability to move or speak for up to several minutes during sleep-wake transitions (1-2).
    [Show full text]
  • Orexin Reverses Cholecystokinin-Induced Reduction in Feeding
    ORIGINAL ARTICLE Orexin reverses cholecystokinin-induced reduction in feeding A. Asakawa,1 A. Inui,1 T. Inui,2 G. Katsuura,3 M. A. Fujino4 and M. Kasuga1 1Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan 2Inui Clinic, Osaka, Japan 3Shionogi Research Laboratories, Shionogi & Co Ltd, Shiga, Japan 4First Department of Internal Medicine, Yamanashi Medical University, Yamanashi, Japan Aim: This study was designed to investigate the effect of orexin on anorexia induced by cholecystokinin (CCK), a peripheral satiety signal. Methods: We administered orexin A (0.01±1 nmol/mouse) and CCK-8 (3 nmol/mouse) to mice. Food intake was measured at different time-points: 20 min, 1, 2 and 4 h post-intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administrations. Results: Intracerebroventricular-administered orexin significantly increased food intake in a dose-dependent man- ner. The inhibitory effect of i.p.-administered CCK-8 on food intake was significantly negated by the simultaneous i.c.v. injection of orexin in a dose-dependent manner. Conclusions: Orexin reversed the CCK-induced loss of appetite. Our results indicate that orexin might be a promising target for pharmacological intervention in the treatment of anorexia and cachexia induced by various diseases. Keywords: orexin, cholecystokinin, mice, food intake, anorexia Received 28 March 2002; returned for revision 20 May 2002; revised version accepted 21 June 2002 Introduction However, the relationship between orexin and per- ipheral satiety systems still remains to be determined. Orexin is a hypothalamic neuropeptide identified as a We investigated the effect of orexin on anorexia induced ligand for an orphan G-protein coupled receptor [1±3].
    [Show full text]
  • Perspective Rxpipeline a Pharmacy
    A PHARMACY ON PERSPECTIVE THE RXPIPELINE Understanding changes in the medication market and their impact on cost and care. EnvisionPharmacies continuously monitors the drug pipeline. As treatment options change, we evaluate and share our perspective on the clinical benefits, cost-effectiveness and overall impact to payers, physicians and patients. Our Perspective on the Rx Pipeline report provides insights on what you should expect from your pharmacy partners to get patients the treatment they need. Included in this Edition } Clinical Pipeline } FDA Drug Approvals } New Indications } Upcoming and Recent Generic Launches } FDA Safety Update } Drug Shortages and Discontinuations 1 | A PHARMACY PERSPECTIVE ON THE RXPIPELINE • OCTOBER 2019 Clinical Pipeline PIPELINE STAGE R & D FDA In Market Off Patent Open Source Off Approved Brand Exclusive Generic Alternative Market crizanlizumab SEG101 Manufacturer: Novartis Indication/Use: Sickle cell disease Dosage Form: Infusion Pipeline Stage: PDUFA 1/2020 Sickle cell disease is a debilitating genetic blood disorder that affects approximately 100,000 Americans.[1] Patients with sickle cell disease can suffer from vaso-occlusive crises (VOCs) that are incredibly painful and can cause irreversible tissue infarction and vasculopathy. VOCs are also associated with increased morbidity and mortality. [2] Hydroxyurea and pharmacy-grade L-glutamine are the only two FDA-approved pharmacotherapies currently available for the prevention of VOCs.[3] Crizanlizumab is a monoclonal antibody that works through selectin
    [Show full text]
  • [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites
    DMD Fast Forward. Published on November 3, 2020 as DOI: 10.1124/dmd.120.000229 This article has not been copyedited and formatted. The final version may differ from this version. Title Page Title: Disposition and Metabolism of [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites Authors: Downloaded from Takashi Ueno, Tomomi Ishida, Jagadeesh Aluri, Michiyuki Suzuki, Carsten T. Beuckmann, Takaaki Kameyama, Shoji Asakura, Kazutomi Kusano dmd.aspetjournals.org Affiliation: Eisai Co., Ltd., Ibaraki, Japan (T.U., T.I., C.B., T.K., S.A., K.K.) Eisai Inc., Woodcliff Lake, NJ, U.S. (J.A.) EA Pharma Co., Ltd., Tokyo, Japan (M.S.) at ASPET Journals on September 24, 2021 1 DMD Fast Forward. Published on November 3, 2020 as DOI: 10.1124/dmd.120.000229 This article has not been copyedited and formatted. The final version may differ from this version. Running Title Page Running title: ADME properties of lemborexant in humans Corresponding Author: Takashi Ueno Downloaded from Drug Metabolism and Pharmacokinetics, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Phone: +81-29-847-5658 dmd.aspetjournals.org FAX: +81-29-847-5672 E-mail: [email protected] Number of text pages: 35 at ASPET Journals on September 24, 2021 Number of tables: 5 Number of figures: 3 Number of references: 23 Number of words in the Abstract: 249 Number of words in the Introduction: 665 Number of words in the Discussion: 1241 2 DMD Fast Forward. Published on November 3, 2020 as DOI: 10.1124/dmd.120.000229 This article has not been copyedited and formatted.
    [Show full text]
  • Clinical Pharmacology of Daridorexant, a Novel Dual Orexin Receptor Antagonist
    Clinical pharmacology of daridorexant, a novel dual orexin receptor antagonist Inauguraldissertation zur Erlangung der Würde eines Dr. sc. med. Vorgelegt der Medizinischen Fakultät der Universität Basel Von Clemens Mühlan aus 4055 Basel, Schweiz Basel, 2021 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Medizinischen Fakultät auf Antrag von Prof. Dr. Stephan Krähenbühl Prof. Dr. Matthias Liechti Dr. Alexander Jetter Dr. Jasper Dingemanse Basel, 24. Februar 2021 Dekan Prof. Dr. Primo Leo Schär 2 of 118 TABLE OF CONTENTS LIST OF ABBREVIATIONS AND ACRONYMS ............................................................4 ACKNOWLEDGEMENTS .................................................................................................8 SUMMARY .........................................................................................................................9 1 BACKGROUND AND INTRODUCTION ................................................................15 1.1 Insomnia .......................................................................................................15 1.2 The orexin system as a therapeutic target .....................................................18 1.3 Review of orexin receptor antagonists .........................................................20 1.4 Selective vs dual orexin receptor antagonism ..............................................23 1.5 Orexin receptor antagonists available in clinical practice ............................24 1.6 Orexin receptor
    [Show full text]
  • Neuropeptides Controlling Energy Balance: Orexins and Neuromedins
    Neuropeptides Controlling Energy Balance: Orexins and Neuromedins Joshua P. Nixon, Catherine M. Kotz, Colleen M. Novak, Charles J. Billington, and Jennifer A. Teske Contents 1 Brain Orexins and Energy Balance ....................................................... 79 1.1 Orexin............................................................................... 79 2 Orexin and Feeding ....................................................................... 80 3 Orexin and Arousal ....................................................................... 83 J.P. Nixon • J.A. Teske Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA C.M. Kotz (*) Veterans Affairs Medical Center, GRECC (11 G), Minneapolis, MN, USA Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA e-mail: [email protected] C.M. Novak Department of Biological Sciences, Kent State University, Kent, OH, USA C.J. Billington Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA Veterans Affairs Medical Center, Endocrine Unit (111 G), Minneapolis, MN, USA Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108, USA H.-G. Joost (ed.), Appetite Control, Handbook of Experimental Pharmacology 209, 77 DOI 10.1007/978-3-642-24716-3_4, # Springer-Verlag Berlin Heidelberg 2012 78 J.P. Nixon et al. 4 Orexin Actions on Endocrine and Autonomic Systems ................................. 84 5 Orexin, Physical Activity, and Energy Expenditure ....................................
    [Show full text]
  • Overcoming Barriers to the Diagnosis and Treatment of Insomnia
    Overcoming Barriers to the Diagnosis and Treatment of Insomnia Thomas Roth, PhD Disclosure Note: This CME activity includes discussion about medications not approved by the US Food and Drug Administration and uses of medications outside of their approved labeling. CONTINUING MEDICAL EDUCATION LEARNING OBJECTIVES entity producing, marketing, re-selling enduring material for a maximum of 1.0 • Apply evidence-based diagnostic or distributing health care goods or ser- AMA PRA Category 1 credit(s)™. Physi- guidelines for patients who have clini- vices consumed by, or used on, patients. cians should claim only the credit com- cal features consistent with insomnia Mechanisms are in place to identify and mensurate with the extent of their par- resolve any potential conflict of interest ticipation in the activity. CME is available • Use evidence-based guidelines to prior to the start of the activity. In addi- September 1, 2020 to August 31, 2021. develop comprehensive treatment tion, any discussion of off-label, experi- plans that include cognitive-behav- mental, or investigational use of drugs or METHOD OF PARTICIPATION ioral therapy, pharmacologic treat- devices will be disclosed by the faculty. PHYSICIANS: To receive CME credit, ment, and combination therapies please read the journal article and, on to achieve optimal outcomes Dr. Roth discloses that he is on the advi- sory boards for Merck, Eisai, Jazz, Idorsia completion, go to www.pceconsortium. • Identify basic elements of cognitive- and Janssen. org/insomnia2 to complete the online behavioral therapy for insomnia post-test and receive your certificate of Gregory Scott, PharmD, RPh, editorial completion. • Differentiate among medications support, discloses he has no real or ap- FDA-approved for treating insomnia parent conflicts of interests to report.
    [Show full text]
  • Calcitonin Gene-Related Peptide Facilitates Sensitization of The
    Zhang et al. The Journal of Headache and Pain (2020) 21:72 The Journal of Headache https://doi.org/10.1186/s10194-020-01145-y and Pain RESEARCH ARTICLE Open Access Calcitonin gene-related peptide facilitates sensitization of the vestibular nucleus in a rat model of chronic migraine Yun Zhang1, Yixin Zhang1*, Ke Tian2, Yunfeng Wang1, Xiaoping Fan1, Qi Pan1, Guangcheng Qin3, Dunke Zhang3, Lixue Chen2 and Jiying Zhou1 Abstract Background: Vestibular migraine has recently been recognized as a novel subtype of migraine. However, the mechanism that relate vestibular symptoms to migraine had not been well elucidated. Thus, the present study investigated vestibular dysfunction in a rat model of chronic migraine (CM), and to dissect potential mechanisms between migraine and vertigo. Methods: Rats subjected to recurrent intermittent administration of nitroglycerin (NTG) were used as the CM model. Migraine- and vestibular-related behaviors were analyzed. Immunofluorescent analyses and quantitative real- time polymerase chain reaction were employed to detect expressions of c-fos and calcitonin gene-related peptide (CGRP) in the trigeminal nucleus caudalis (TNC) and vestibular nucleus (VN). Morphological changes of vestibular afferent terminals was determined under transmission electron microscopy. FluoroGold (FG) and CTB-555 were selected as retrograde tracers and injected into the VN and TNC, respectively. Lentiviral vectors comprising CGRP short hairpin RNA (LV-CGRP) was injected into the trigeminal ganglion. Results: CM led to persistent thermal hyperalgesia, spontaneous facial pain, and prominent vestibular dysfunction, accompanied by the upregulation of c-fos labeling neurons and CGRP immunoreactivity in the TNC (c-fos: vehicle vs. CM = 2.9 ± 0.6 vs.
    [Show full text]
  • Significance of the Orexinergic System in Modulating Stress-Related
    Cohen et al. Translational Psychiatry (2020) 10:10 https://doi.org/10.1038/s41398-020-0698-9 Translational Psychiatry ARTICLE Open Access Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder Shlomi Cohen1,2,MichaelA.Matar1, Ella Vainer1, Joseph Zohar3,4,ZeevKaplan1 and Hagit Cohen1,2 Abstract Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post- traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; untreated rats.
    [Show full text]
  • Orexins, Sleep, and Blood Pressure
    Current Hypertension Reports (2018) 20: 79 https://doi.org/10.1007/s11906-018-0879-6 SLEEP AND HYPERTENSION (SJ THOMAS, SECTION EDITOR) Orexins, Sleep, and Blood Pressure Mariusz Sieminski1 & Jacek Szypenbejl1 & Eemil Partinen2,3 Published online: 10 July 2018 # The Author(s) 2018 Abstract Purpose of Review The aim of this review was to summarize collected data on the role of orexin and orexin neurons in the control of sleep and blood pressure. Recent Findings Although orexins (hypocretins) have been known for only 20 years, an impressive amount of data is now available regarding their physiological role. Hypothalamic orexin neurons are responsible for the control of food intake and energy expenditure, motivation, circadian rhythm of sleep and wake, memory, cognitive functions, and the cardiovascular system. Multiple studies show that orexinergic stimulation results in increased blood pressure and heart rate and that this effect may be efficiently attenuated by orexinergic antagonism. Increased activity of orexinergic neurons is also observed in animal models of hypertension. Summary Pharmacological intervention in the orexinergic system is now one of the therapeutic possibilities in insomnia. Although the role of orexin in the control of blood pressure is well described, we are still lacking clinical evidence that this is a possibility for a new approach in the treatment of cardiovascular diseases. Keywords Orexin . Hypocretin . Blood pressure . Sleep . Narcolepsy . Autonomic nervous system Introduction cardiovascular system. With such a variety of functions, orexins appear to be a promising target for therapeutic in- We are celebrating the twentieth anniversary of the discov- terventions aimed at solving the most pivotal health prob- ery of hypocretins/orexins.
    [Show full text]